CN109896991B - Opioid receptor antagonist and application and pharmaceutical composition thereof - Google Patents
Opioid receptor antagonist and application and pharmaceutical composition thereof Download PDFInfo
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Abstract
The invention discloses a compound with a structure shown in a general formula (I), and a pharmaceutically acceptable salt, a hydrate or a metabolite formed by metabolism in any form of the compound; the use of a compound of formula (I) for the prevention and/or treatment of Alzheimer's related diseases and conditions; a pharmaceutical composition for preventing and/or treating Alzheimer's disease-related diseases and symptoms, which comprises a compound having a structure represented by the general formula (I); compared with the prior art, the opioid receptor antagonist has ideal drug half-life and excellent Alzheimer related disease treatment activity, and is a more ideal Alzheimer related disease drug compared with the existing compound.
Description
Technical Field
The present invention relates to opioid receptor antagonists and their use and pharmaceutical compositions for the prevention and/or treatment of diseases and conditions associated with alzheimer's disease.
Background
Alzheimer's Disease (AD) is a degenerative disease of the central nervous system and one of the most prominent causes of dementia. The currently most important hypothesis for the pathogenesis of alzheimer's disease is the β -amyloid (a β) hypothesis. The hypothesis is that the main component A beta of amyloid plaques plays a fundamental role in the occurrence of Alzheimer's disease, under the long-term action of complex genetic and environmental factors, neurons abnormally produce A beta in large quantity, accumulate to form A beta oligomers and amyloid plaques, and the A beta directly or indirectly acts on neurons and glial cells through a series of cascade reactions (including free radical reactions, mitochondrial oxidative damage, inflammatory reactions and the like), so that synaptic dysfunction and neuron injury are caused, microglia and astrocyte activation are caused, the formation of neurofibrillary silk tangles is accelerated, and cognitive impairment is caused after long-term action.
Currently, FDA approved drugs for the treatment of alzheimer's disease include Donepezil (Donepezil), Rivastigmine (Rivastigmine), Galantamine (Galantamine), Tacrine (Tacrine), Memantine (Memantine), the first four of which are cholinesterase (AChE) inhibitors, while Memantine is an antagonist of NMDA receptors, a subtype of glutamate receptors. These drugs can only reduce the worsening of the clinical symptoms of moderate to severe alzheimer's disease to a certain extent, but do not improve memory or cure effectively, and the market demand is far from being met. Therefore, the development of new target AD drugs is very necessary.
At least 8 subtypes exist for opioid receptors, and at least 4 subtypes exist within the central nervous system: mu Opioid Receptor (MOR), Kappa Opioid Receptor (KOR), opioid receptor (DOR), sigma opioid receptor. Among them, the major ones are μ, κ, and the three subtypes. Opioid receptors belong to the general class of G protein-coupled receptors, which share the same basic structure: an extracellular amino-terminal region, seven transmembrane domains and an intracellular carboxy-terminal tail region. It has been disclosed that opioid receptors are very valuable new targets for developing therapeutic drugs for alzheimer's disease, opioid receptor antagonists (such as NTI, naltrexone) can significantly reduce the cleavage activity of beta-secretase and gamma-secretase for APP in transgenic mice, thereby reducing the level of beta amyloid, and the learning and memory of mice in behavioral tests are also significantly improved.
For example, chinese patent CN104844471B discloses a compound as a DOR receptor antagonist, and although experiments show that these compounds have better activity, their half-life of the drug is too short or too long compared to the ideal case. When these compounds are considered as a whole, they cannot be considered as ideal therapeutic agents for Alzheimer's disease.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art and provide an improved opioid receptor antagonist which has ideal drug half-life and excellent therapeutic activity for Alzheimer related diseases.
The invention also provides the application of the compound with the structure shown in the general formula (I), the pharmaceutically acceptable salt, the hydrate or the metabolite formed by metabolism in any form in preventing and/or treating the diseases and symptoms related to the Alzheimer disease.
The invention also provides a pharmaceutical composition.
In order to solve the technical problems, the invention adopts a technical scheme as follows:
a compound with a structure shown in a general formula (I), a pharmaceutically acceptable salt, a hydrate or a metabolite formed by metabolism in any form,
wherein:
R1is selected from-CONH2Or a hydroxyl group;
R2selected from hydrogen, fluorine, chlorine or bromine;
x, Y are independently selected from CH or N;
R3selected from C1-6 substituted alkyl, C1-6 alkoxy or-CON (R)8)R9Wherein R is8、R9Independently selected from C1-6 alkyl or C1-6 substituted alkyl, or R8、R9A 5-8 membered nitrogen-containing heterocyclic ring is formed with the connected nitrogen atom; the nitrogen-containing heterocycle is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, fluoro, chloro, bromo and C1-6 alkyl;
R4、R5independently selected from hydrogen, fluorine, chlorine, bromine or alkoxy of C1-6;
the substituent in the C1-6 substituted alkyl is one or more and is selected from fluorine, chlorine, bromine or hydroxyl;
R6、R7one of them is hydroxy and the other is selected from hydrogen or C1-6 alkyl;
when R is6、R7When one of them is hydrogen, the other substituents satisfy the following condition:
R4、R5not hydrogen at the same time; or, R3Is not-CON (R)8)R9Wherein R is8、R9Is C1-6 alkyl.
According to some preferred aspects of the present invention, the compound is one selected from the group consisting of structures represented by general formula (II) or general formula (III),
in the formula (II), R6Is C1-6 alkyl; in the formulae (II) and (III), R1Is selected from-CONH2Or a hydroxyl group;
R2selected from hydrogen, fluorine, chlorine or bromine;
x, Y are independently selected from CH or N;
R3selected from C1-6 substituted alkyl, C1-6 alkoxy or-CON (R)8)R9Wherein R is8、R9Independently selected from C1-6 alkyl or C1-6 substituted alkyl, or R8、R9A 5-8 membered nitrogen-containing heterocyclic ring is formed with the connected nitrogen atom; the nitrogen-containing heterocycle is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, fluoro, chloro, bromo and C1-6 alkyl;
R4、R5independently selected from hydrogen, fluorine, chlorine, bromine or alkoxy of C1-6;
the substituent in the C1-6 substituted alkyl is one or more and is selected from fluorine, chlorine, bromine or hydroxyl;
wherein, in the formula (III), R4、R5Not hydrogen at the same time; or, R3Is not-CON (R)8)R9Wherein R is8、R9Is C1-6 alkyl.
According to a further preferred aspect of the present invention, in the general formula (III), R1Is a hydroxyl group; r3Selected from C1-6 substituted alkyl or-CON (R)8)R9Wherein R is8、R9Independently selected from C1-6 alkyl.
According to a particular and preferred aspect of the invention, in formula (ii), X, Y is CH, or CH, N, or N, N; in the formula (III), X, Y is CH, CH or N, N.
Some advantages in the inventionIn a preferred embodiment, the C1-6 alkyl group is-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)CH3、-CH2CH(CH3)2、-CH(CH2CH3)2、-C(CH3)2CH2CH3or-C (CH)3)3；
The alkoxy of C1-6 is-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2CH2CH3、-OCH(CH3)2、-OCH(CH2CH3)2or-OC (CH)3)3；
The substituted alkyl of C1-6 is-CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-C(CH3)2CH2OH、-CH(CH3)CH2OH、-C(CH3)2CH2CH2OH、-C(CH2CH3)(CH3)OH、-C(CH2CH3)2OH、-CF3、-CH2CF3、-CH2CH2CF3、-C(CH3)2CF3、-C(CH3)2CH2CF3。
According to a particular and preferred aspect of the invention, the nitrogen-containing heterocycle is
According to a further preferred aspect of the invention, the nitrogen-containing heterocycle is unsubstituted or substituted para to the nitrogen atom.
In some preferred embodiments of the present invention, the compound is selected from one of the compounds represented by the following structures,
the invention provides another technical scheme that: the application of the compound with the structure shown in the general formula (I), the pharmaceutically acceptable salt, the hydrate or the metabolite formed by metabolism in any form in preventing and/or treating the diseases and symptoms related to the Alzheimer disease.
The invention provides another technical scheme that: a pharmaceutical composition for preventing and/or treating diseases and symptoms related to alzheimer's disease, which comprises the compound having the structure shown in the general formula (i), a pharmaceutically acceptable salt, a hydrate or a metabolite formed by metabolism in any form.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the opioid receptor antagonist has ideal drug half-life and excellent Alzheimer-related disease treatment activity, and is more ideal Alzheimer-related disease drug compared with the existing compound.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "salt" refers to a pharmaceutically acceptable salt of a compound of the invention with an acid, which may be selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or the like.
The term "solvate" refers to a form of a compound of the present invention that forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.
The term "crystalline" refers to the various solid forms formed by the compounds of the present invention, including crystalline forms, amorphous forms.
The term "alkyl" refers to a straight, branched or cyclic saturated hydrocarbon group, which when substituted is generally preferred to have a carbon number of less than 20, wherein cyclic alkyl is often referred to as cycloalkyl, which may be monocyclic or polycyclic, and in the case of polycyclic rings, spiro, fused, bridged, and the like. Specific common alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, cycloheptyl, 2, -methylbutyl and 2, 3-dimethylbutyl, 16-alkyl, 18-alkyl and the like.
The term "aryl" refers to an all-carbon monocyclic or polycyclic aromatic group including phenyl, naphthyl, biphenyl and the like. The aryl group may be substituted or unsubstituted.
The term "heteroaryl" refers to a group of a heteroaromatic system that contains a heteroatom. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. Wherein the mono-heterocyclic group includes, but is not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 3-thiadiazole, oxazole, 1,2, 4-oxadiazole, 1,3, 4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline, etc. Fused heterocyclic groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromene, fluorenone, quinoxaline, 3, 4-dihydronaphthalenone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, and the like. Heteroaryl groups may be substituted and unsubstituted.
The term "halogen" refers to fluorine, chlorine, bromine, iodine. The term "haloalkyl" refers to an alkyl group substituted with at least one halogen atom.
The term "deuterium" is an isotope of hydrogen with an atomic mass 2 times that of the latter and is more strongly bound to carbon. Deuterated "and" deuterium "indicate that hydrogen is replaced with deuterium at the indicated position. One "deuterated substituent" is a substituent wherein at least one hydrogen is replaced with deuterium enriched in the specified percentage.
The term "heterocyclyl" refers to a cyclic group containing at least one heteroatom, wherein the heteroatom is nitrogen, oxygen, sulfur, and the like. The heterocyclic group includes a mono-heterocyclic group and a poly-heterocyclic group. Heterocyclyl groups may be substituted and unsubstituted. The substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, and cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl, etc.
The term "selectively" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
Example 1 preparation of compound (1):
preparation of Compounds 1-2:
compound 1-1(4.900g,20.50mmol) (70%) was placed in a 100mL round-bottomed flask and potassium hexacyanoferrate trihydrate (2.598g,6.150mmol), Pd (dppf) Cl was added2(1.498g,2.050mmol), anhydrous potassium carbonate (2.886g,20.91mmol) and TBAB (6.873g,21.32mmol), replaced with nitrogen three times, then anhydrous DMF60ml was added, and the mixture was stirred under reflux for 6 hours. Concentrating, separating the crude product by column chromatography to obtain 500mg, and directly using in the next step.
Preparation of Compounds 1-3:
compound 1-2(0.500g,2.703mmol) was placed in a 100ml round bottom flask, 15ml of phosphorus oxychloride was added, after dissolution, cooling was carried out in an ice-water bath, DMF (0.494g,6.758mmol) was slowly added dropwise, and after completion of the addition, stirring was carried out under reflux with heating. After the reaction is finished, ice water is added for quenching, ethyl acetate is used for extraction, drying and concentration are carried out, and 460mg of the crude product is obtained through column chromatography separation and is directly used in the next step.
Preparation of Compounds 1-5:
compound 1-4(0.738g,2.436mmol) was charged to a 100ml reaction flask, and Compound 1-3(0.460g,2.03mmol), Pd (dppf) Cl, was added2(0.148g,0.20mmol), potassium acetate (0.598g,6.09mmol), 1, 4-dioxane (10ml) and 1ml water, and nitrogen gas is replaced for protection. The reaction was refluxed for 4 hours. After the reaction is completed, the mixture is concentrated and dried, and the crude product is subjected to column chromatography to obtain 300mg of a pure product.
Preparation of Compounds 1-6:
compound 1-5(0.100g,0.27mmol) and 4-methyl-4-hydroxypiperidine (0.053g,0.53mmol) were added to 6mL1, 2-dichloroethane, and stirred at room temperature for 1 hour. Then, sodium borohydride acetate (0.570g,2.68mmol) was added and the reaction was carried out overnight under nitrogen. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, dried, concentrated, and prepared to obtain 40mg, which was used directly in the next step.
Preparation of compound 1:
compounds 1-6(40mg,0.087mmol) were added to 5ml DMSO and cooled in an ice-water bath. After 10min, 0.5mL of hydrogen peroxide and 40mg of potassium carbonate were added. Stir at room temperature overnight. And after the reaction is finished, adding 20mL of water for dilution, extracting twice by using dichloromethane, combining organic phases, washing with water, drying, concentrating, and separating by using a preparation plate to obtain 9mg of the compound 1.1HNMR(400MHz,CD3OD):7.76(m,1H),7.50(m,2H),7.41(m,2H),7.35(m,2H,),4.59(s,3H),3.60-3.55(m,2H),3.44(s,2H),3.37-3.35(m,2H),3.17-3.14(m,2H),2.90-2.87(t,2H),2.34-2.17(m,4H),2.08-2.02(m,1H),1.73-1.70(m,2H),1.42-1.39(m,2H),1.32-1.30(m,6H),1.19(m,3H)。 +ESI-MS m/z 490.2(M+H)。
Example 2 preparation of compound (2):
synthesis of Compound 2-2:
the compound 2-1(1.000g,5.0mmol), piperidine (1.006g,10mmol), TBTU (2.396g,7.5mmol) and DIPEA (1.926g,15mmol) are dissolved in DCM (25ml), and the reaction is completed at room temperature under the protection of nitrogen for 3h.TLC shows that the raw material is completely reacted, and the product is purified by column chromatography to obtain 1.379g, the yield is 97%.
Synthesis of Compounds 2-3:
compound 2-2(0.400g,1.4mmol), pinacol ester of bisboronic acid (0.429g,1.7mmol), KOAc (0.276g,2.8mmol) were added to 25mL1, 4-dioxane, replaced with nitrogen three times, and Pd (dppf) Cl was added2(0.103g,0.14mmol), reacted at 80 ℃ for 3h and then used directly in the next reaction.
Synthesis of Compounds 2-5:
adding into the reaction solution of the compound 2-3Compound 2-4(0.150g,0.57mmol) and water (1ml) were purged with nitrogen, and Pd (dppf) Cl was added2(0.110g,0.15mmol), and then reacted at 80 ℃ for 2h under nitrogen. Then, 0.154g of product is obtained by column chromatography separation, and the yield is 63 percent.
Synthesis of Compounds 2-6:
compound 2-5(0.154g,0.4mmol), 4-hydroxy-4-methylpiperidine (0.082g,0.7mmol) are dissolved in 1, 2-dichloroethane (10ml), stirred for 10min, then NaBH (OAc) is added3(0.602g,2.8mmol), and reacted at room temperature overnight. After the reaction, saturated sodium bicarbonate solution was added, DCM extraction (40ml × 3) was performed, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by thin layer chromatography to obtain 38mg of pure product with a yield of 18%.
Synthesis of Compound 2:
dissolving compound 2-6(0.038g,0.07mmol) in MeOH (4ml), adding NaOH (1ml,2.0N) dropwise, reacting at room temperature for 20min. TLC shows that the raw materials are completely reacted, adjusting the pH to 9-10, extracting with DCM (40 ml. times.2), combining the organic phases, drying over anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.024g pure product with a yield of 70%.1HNMR(400MHz,CD3OD):7.47(d,J＝8.4Hz,2H),7.26(d,J＝8.4Hz,2H),7.11(d,J＝8.4Hz,1H),6.66(m,1H),6.24(d,J＝2.4Hz,1H),4.20(m,1H),3.91(m,1H),3.71(m,3H),3.15(m,2H),2.86(m,2H),2.75(m,2H),2.23(m,4H),1.96-1.74(m,7H),1.60-1.50(m,3H),1.24(s,3H)。 +ESI-MS m/z 491.2(M+H)。
Example 3 preparation of compound (3):
synthesis of Compound 3-2:
add 3-1(0.38g,1.89mmol), 4-fluoropiperidine hydrochloride (0.18g,1.29mmol), TBTU (0.62g,1.93mmol) and DIPEA (0.56mL,3.21mmol) to 30mL of EDCM, stir at room temperature overnight, concentrate, and purify the residue by column chromatography to give 0.4g of product.
Synthesis of Compounds 3-5:
compound 3-2(0.40g,1.40mol), pinacol diboron (0.532g,2.09mol), KOAc (0.35g,3.57mol), Pd (dppf) Cl2(130mg,0.18mmol) was added to 1, 4-dioxane (20ml), purged with nitrogen, and then reacted at 90 ℃ for 3 hours. After the reaction was complete, compound 3-4(0.40g,1.51mmol), Pd (dppf) Cl was added2(69mg,0.09mmol) and 0.5mL of water, and heating to 100 ℃ for 4h under nitrogen replacement. Concentrating, and performing column chromatography to obtain 0.2g of product.
Synthesis of Compound 3:
compound 3-5(0.20g,0.46mmol) and 4-methyl-4-hydroxypiperidine (0.095g,0.82mmol) are dissolved in dichloromethane, stirred for 30min, and NaBH (AcO) is added3(0.92g,4.34mmol), stirred overnight at room temperature, and saturated NaHCO was added3The solution is extracted three times with DCM, the organic phases are combined, concentrated, the residue is dissolved with 5mL of methanol, 10mL of NaOH (1M) solution is added, after half an hour, the pH is adjusted to be neutral, the aqueous phase is extracted three times with DCM, the organic phases are combined, dried and concentrated, and the residue is purified by thin layer chromatography to obtain 10mg of the product.1HNMR(CD3OD,400MHz):7.52(d,J＝8.0,2H),7.27(d,J＝8.0,2H),7.11(m,1H),6.66(m,1H),6.24(m,1H),4.59(m,1H),3.92～3.65(m,7H),3.23(m,2H),2.97(m,2H),2.76(m,2H),2.25(m,4H),1.73(m,8H),1.30(m,3H)。 +ESI-MS m/z493.2(M+H)。
Example 4 preparation of compound (4):
synthesis of Compound 4-2:
compound 4-1(1.0g,4.97mmol), 4-methyl-4-hydroxypiperidine (0.82g,7.12mmol), TBTU (2.10g,6.54mmol) were placed in a bottle, 30mL of CCM, DIPEA (3.0mL,17.22mmol) were added, the mixture was stirred at room temperature overnight, the reaction solvent was distilled off, and the residue was purified by column chromatography to give 1.9g of the product.
Synthesis of Compounds 4-3:
compound 4-2(1.9g,6.37mol), pinacol diboron (2.2g,8.66mol), potassium acetate (1.7g,7.13mol), Pd (dppf) Cl2(310mg,0.42mmol) was added to 1, 4-dioxane (60ml), and the mixture was reacted at 90 ℃ for 3 hours under nitrogen substitution protection.
Synthesis of Compounds 4-5:
to the 4-3 reaction solution were added compound 4-4(0.30g,1.13mmol), Pd (dppf) Cl2(98mg,0.13mmol) and 0.5mL of water were reacted with nitrogen gas, and the mixture was heated to 100 ℃ for 4 hours. The reaction solvent was distilled off, and the residue was subjected to column chromatography to obtain 0.31g of a product.
Preparation of compound 4:
compound 4-5(0.21g,0.47mmol), 4-methyl-4-hydroxypiperidine (0.105g,0.91mmol) was dissolved in dichloromethane, stirred for 30min, and NaBH (AcO) was added3(0.89g,4.20mmol), stirred overnight at room temperature, and saturated NaHCO was added3Extracting the aqueous phase with DCM-IPA (3:1) mixed solvent for three times, mixing the organic phases, evaporating the organic phase solvent, dissolving the residue with 5mL of methanol,adding 10mL NaOH (1M) solution, adjusting pH to neutral after half an hour, extracting the water phase three times with DCM-IPA (3:1) mixed solvent, combining the organic phases, evaporating the organic phases, and purifying the residue by thin layer chromatography to obtain 17mg of the product.1HNMR(CD3OD,400MHz):7.48(m,2H),7.27(m,2H),7.11(m,1H),6.66(m,1H),6.24(m,1H),4.58(m,2H),3.72(m,1H),3.54(m,2H),3.14(m,2H),2.87(m,2H),2.75(m,2H),2.25(m,3H),1.73(m,5H),1.58(m,2H),1.30(m,8H)。 +ESI-MSm/z 505.3(M+H)。
Example 5 preparation of compound (5):
synthesis of Compound 5-2:
compound 5-1(1.00g,4.6mmol), piperidine (0.924g,9.1mmol), TBTU (2.199g,6.8mmol) and DIPEA (1.768g,13.7mol) were dissolved in DCM (30ml) and reacted at room temperature for 3h under nitrogen protection, followed by column chromatography to give 1.210g of product in 87% yield.
Synthesis of Compounds 5-3:
compound 5-2(0.300g,1.0mmol), pinacol ester of bisboronic acid (0.328g,1.3mmol) and KOAc (0.195g,2.0mmol) were added to 1, 4-dioxane (25ml), the mixture was replaced with nitrogen, and Pd (dppf) Cl was added2(0.073g,0.1mmol) and reacted at 95 ℃ under nitrogen protection for 3h.
Synthesis of Compounds 5-5:
to the reaction mixture of Compound 5-3, Compound 5-4(0.150g,0.57mmol) and water (1ml) were added, the mixture was purged with nitrogen, and Pd (dppf) Cl was added2(0.120g,0.16mmol), reacting for 2.5h at 80 ℃ under the protection of nitrogen replacement, and then separating by column chromatography to obtain 0.255g of product with the yield of 99%.
Synthesis of Compounds 5-6:
compound 5-5(0.255g,0.6mmol), 4-hydroxy-4-methylpiperidine (0.130g,1.1mmol) were dissolved in 1, 2-dichloroethane (16ml), purged with nitrogen, stirred for 10min, and NaBH (OAc) was added3(0.960g,4.5mmol), overnight at room temperature TLC showed small amount of unreacted starting material, saturated sodium bicarbonate solution was added, DCM extracted (50 ml. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 0.330g of crude product.
Synthesis of Compound 5:
dissolving the compound 5-6(0.330g, crude product) in MeOH (9ml), dropwise adding NaOH (4ml,2N), reacting at room temperature for 15min, performing TLC to show that the raw material is completely reacted, adjusting the pH to be alkalescent, performing DCM extraction (50ml multiplied by 2), combining organic phases, drying over anhydrous sodium sulfate, concentrating, and performing thin layer chromatography to purify to obtain 0.059g of a product.1HNMR(400MHz,CD3OD):7.43(t,J＝7.2Hz,1H),7.12-7.03(m,3H),6.66(m,1H),6.25(d,J＝2.4Hz,1H),4.20(m,1H),3.92(m,1H),3.65(m,3H),3.43(m,1H),3.25(m,1H),3.07(m,2H),2.85(m,2H),2.72(m,2H),2.23(m,4H),1.95-1.85(m,2H),1.74(m,4H),1.57(m,2H),1.25(s,3H)。 +ESI-MS m/z 510.2(M+H)。
Example 6 preparation of compound (6):
synthesis of Compound 6-2:
the compound 6-1(1.000g,4.2mmol), piperidine (0.616g,8.4mmol), TBTU (2.032g,6.3mmol) and DIPEA (1.633g,0.015mol) were dissolved in DCM (25ml), magnetically stirred under nitrogen protection, reacted at room temperature for 3h, and then purified by column chromatography to give 1.167g of product with 95% yield.
Synthesis of Compounds 6-3:
compound 6-2(0.300g,1mmol), pinacol ester of bisboronic acid (0.313g,1.2mmol), KOAc (0.202g,2.1mmol) were added to 1, 4-dioxane (20ml), magnetically stirred, replaced with nitrogen, and Pd (dppf) Cl was added2(0.075g,0.1mmol), nitrogen protection, heating up to 83 ℃ for 4h.
Synthesis of Compounds 6-5:
to the reaction mixture of Compound 6-3, 6-4(0.150g,0.57mmol) and water (1ml) were added, and the mixture was magnetically stirred, purged with nitrogen, and then Pd (dppf) Cl was added2(0.120g,0.16mmol), nitrogen substitution protection, heating up to 83 ℃ and reaction for 2h. The product of 0.213g is obtained by column chromatography separation, and the yield is 84 percent.
Synthesis of Compounds 6-6:
compound 6-5(0.213g,0.5mmol), 4-hydroxy-4-methylpiperidine (0.111g,0.7mmol) were dissolved in 1, 2-dichloroethane (12ml), purged with nitrogen, stirred for 15min, and NaBH (OAc) was added3(0.818g,3.9mmol), and reacted at room temperature overnight. Saturated sodium bicarbonate solution and DCM (50ml/40ml) were added, the layers separated, the aqueous layer extracted with DCM (50 ml. times.2), the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give 200mg of crude product.
Synthesis of Compound 6:
dissolving compound 6-6(0.2g, 0.4mmol) in MeOH (6ml), adding dropwise NaOH (2ml,2.0N), reacting at room temperature for 15min, TLC to show that the raw material is completely reacted, adjusting pH to weak alkalinity, and extracting with DCM (40ml)X 2), combining organic phases, drying by anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.070g of product.1HNMR(400MHz,CD3OD):7.24(m,1H),7.16(m,1H),7.12(d,J＝8.0Hz,1H),6.66(m,1H),6.25(d,J＝2.4Hz,1H),3.60(m,4H),3.36(s,2H),3.07(m,2H),2.85(m,2H),2.72(m,2H),2.24(m,4H),1.74(m,4H),1.25(m,6H),1.16(t,J＝6.8Hz,3H)。 +ESI-MS m/z 500.2(M+H)。
Example 7 preparation of compound (7):
synthesis of Compound 7-2:
dissolving the compound 7-1(1.000g and 5mmol), piperidine (0.847g and 10mmol), TBTU (2.396g and 7.5mmol) and DIPEA (1.926g and 15mmol) in DCM (20ml), reacting for 3h at room temperature under the protection of nitrogen, carrying out magnetic stirring, and carrying out TLC to show that the raw materials are completely reacted, and carrying out column chromatography purification to obtain 1.274g of a product with the yield of 95%.
Synthesis of Compounds 7-3:
compound 7-2(0.400g,1.5mmol), pinacol ester of bisboronic acid (0.454g,1.8mmol), KOAc (0.294g,3mmol) were added to 1, 4-dioxane (20ml), magnetically stirred, replaced with nitrogen, and Pd (dppf) Cl was added2(0.109g,0.15mmol), reacting for 3h under nitrogen protection and heating up to 83 ℃, and the reaction liquid is reserved after the completion of the reaction by TLC.
Synthesis of Compounds 7-5:
compound 7-3 (the reaction solution in the previous step), 7-4(0.150g,0.57mmol) and water (1ml) were mixed, magnetically stirred, replaced with nitrogen, and Pd (dppf) Cl was added2(0.150g,0.2mmol), nitrogen replacement protection, heating up to 85 ℃ for reaction for 2.5h, TLC shows that the raw material 4 completely reacts, and column chromatography separation is carried out to obtain 0.184g of product with the yield of 77%.
Synthesis of Compounds 7-6:
compound 7-5(0.184g,0.4mmol), 4-hydroxy-4-methylpiperidine (0.102g,0.9mmol) were dissolved in 1, 2-dichloroethane (12ml), purged with nitrogen, stirred for 10min, and NaBH (OAc) was added3(0.747g,3.5mmol) and reacted at room temperature overnight, TLC showed a small amount of unreacted starting material, saturated sodium bicarbonate solution and DCM (50ml/40ml) were added, the aqueous phase was separated, extracted with DCM (50 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and isolated by thin layer chromatography to give 0.136g of pure product with a yield of 66%.
Synthesis of compound 7:
dissolving the compound 7-6(0.136g,0.26mmol,1.0eq) in MeOH (5ml), dropwise adding NaOH (2ml,2.0N), reacting at room temperature for 1h, adjusting the pH to be weakly alkaline as shown by TLC, extracting DCM (50ml multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.074g of pure product with the yield of 60%.1HNMR(400MHz,CD3OD):7.46(d,J＝8.4Hz,2H),7.25(d,J＝8.0Hz,2H),6.64(m,1H),6.23(d,J＝2.4Hz,1H),4.59(s,1H),3.74-3.65(m,4H),3.45(m,2H),3.06(m,2H),2.83(m,2H),2.73(m,2H),2.23(m,4H),1.72(m,8H),1.59(m,2H),1.23(s,3H)。 +ESI-MS m/z 476.2(M+H)。
Example 8 preparation of compound (8):
synthesis of Compound 8-2:
compound 8-1(1.000g,5mmol), N-methylisopropylamine (0.728g,10mmol), TBTU (2.396g,7.5mmol) and DIPEA (1.926g,15mmol) were dissolved in DCM (25ml), magnetically stirred under nitrogen, reacted at room temperature for 3h.TLC showed complete reaction of the starting materials, and purified by column chromatography to give 1.400g of product.
Synthesis of Compounds 8-3:
compound 8-2(0.500g,2mmol), pinacol ester of bisboronic acid (0.595g,2.3mmol), KOAc (0.383g,3.9mmol) were added to 1, 4-dioxane (20ml), magnetically stirred, replaced with nitrogen, and Pd (dppf) Cl was added2(0.143g,0.2mmol), nitrogen protection, heating up to 83 ℃ and reacting for 3h.
Synthesis of Compounds 8-5:
to the reaction mixture of compound 8-3 were added 8-4(0.150g,0.57mmol) and water (1ml), and the mixture was purged with nitrogen and then added Pd (dppf) Cl2(0.120g,0.16mmol), nitrogen replacement protection, heating up to 85 ℃ for reaction for 2h, TLC shows that the raw material 4 completely reacts, and column chromatography separation is carried out to obtain 0.174g of product with the yield of 75%.
Synthesis of Compounds 8-6:
compound 8-5(0.174g,0.4mmol), 4-hydroxy-4-methylpiperidine (0.099g,0.9mmol) were dissolved in 1, 2-dichloroethane (12ml), purged with nitrogen, stirred for 30min, and NaBH (OAc) was added3(0.909g,4.3mmol), reaction overnight at room temperature TLC showed small amount of unreacted raw material, saturated sodium bicarbonate solution and DCM (50ml/40ml) were added, the liquid was separated, the aqueous phase was extracted with DCM (40 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by thin layer chromatography to give 0.038g of pure product with a yield of 19%.
Synthesis of compound 8:
chemical combinationDissolving 8-6(0.038g,0.08mmol) in MeOH (4ml), adding NaOH (2ml,2.0N) dropwise, reacting at room temperature for 1h, adjusting pH to be alkalescent, extracting DCM (40ml × 2) after TLC shows that the raw materials are completely reacted, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.026g of pure product with yield of 75%.1HNMR(400MHz,CD3OD):7.44(m,2H),7.24(m,2H),7.09(d,J＝8.4Hz,1H),6.65(m,1H),6.23(d,J＝0.8Hz,1H),4.03(m,1H),3.73(m,2H),3.13(m,2H),2.96-2.86(m,5H),2.74(s,2H),2.22(m,4H),1.72(m,4H),1.22(m,9H)。 +ESI-MS m/z464.2(M+H)。
Example 9 preparation of compound (9):
synthesis of Compound 9-2:
the compound 9-1(0.336g,1.7mmol), N-methyl-N-2, 2, 2-trifluoromethylethylamine (0.500g,3.3mmol,2.0eq), TBTU (0.805g,2.5mmol) and DIPEA (0.647g,5mmol) were dissolved in DCM (25ml), and under nitrogen protection, magnetically stirred, reacted at room temperature overnight, TLC showed complete reaction of the starting material, column chromatography purification gave 0.440g of product, 88% yield.
Synthesis of Compounds 9-3:
compound 9-2(0.440g,1.5mmol), pinacol diboron (0.453g,1.8mmol), KOAc (0.292g,3.0mmol) were added to 1, 4-dioxane (20ml), magnetically stirred, replaced with nitrogen, and Pd (dppf) Cl was added2(0.109g,0.15mol), reacting for 3h under the protection of nitrogen, raising the temperature to 83 ℃, and keeping the reaction liquid for later use by TLC.
Synthesis of Compounds 9-5:
9-4(0.200g,0.76mmol) and water (1ml) were added to a reaction solution of the compound 9-3, magnetically stirred, purged with nitrogen, and added with Pd (dppf) Cl2(0.150g,0.2mmol), reacting for 3h under the protection of nitrogen, heating up to 83 ℃, and performing column chromatography to obtain 0.245g of product with the yield of 72 percent, wherein the raw material 4 is completely reacted.
Synthesis of Compounds 9-6:
compound 9-5(0.245g,0.8mmol), 4-hydroxy-4-methylpiperidine (0.190g,1.6mmol) were dissolved in 1, 2-dichloroethane (12ml), purged with nitrogen, stirred for 30min, NaBH (OAc) was added3(1.748g,8.2mmol), reaction at room temperature overnight. TLC shows complete reaction of raw material, saturated sodium bicarbonate solution and DCM (50ml/40ml) are added, liquid separation is carried out, aqueous phase is extracted with DCM (40 ml. times.2), organic phase is combined, dried by anhydrous sodium sulfate, concentrated, and separated by thin layer chromatography to obtain 0.060g pure product with yield of 14%.
Synthesis of compound 9:
dissolving the compound 9-6(0.060g,0.1mmol) in MeOH (5ml), adding NaOH (2ml,2.0N) dropwise, reacting at room temperature for 1h, TLC shows that the raw materials are completely reacted, adjusting the PH to be alkalescent, DCM extracting (40ml multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.013g of pure product with the yield of 23%.1HNMR(400MHz,CD3OD):7.46(m,2H),7.23(m,2H),7.07(d,J＝8.0Hz,1H),6.61(m,1H),6.20(d,J＝0.8Hz,1H),4.33(m,2H),3.42(m,2H),3.16(m,3H),2.83-2.60(m,6H),2.19(m,4H),1.65(m,4H),1.19(s,3H)。ESI-MS m/z +504.2(M+H)。
Example 10 preparation of compound (10):
synthesis of Compound 10-2:
dissolving isopropanol (1.2g,19.97mmol) in anhydrous DMF, adding NaH (1.21g,30.25mmol), stirring at room temperature for 30min, adding 10-1(2.0g,10.34mmol), stirring at room temperature overnight, evaporating DMF, diluting the residue with water, extracting the aqueous phase three times with EA, combining the organic phases, washing the organic phases with saline solution three times, collecting the organic phases, evaporating the organic phases, and purifying the residue by column chromatography to obtain 0.45g of the product.
Synthesis of Compounds 10-5:
compound 10-2(0.45g,2.07mmol), pinacol diboron (0.57g,1.08mmol), KOAc (0.92g,9.37mmol), Pd (dppf) Cl2(65mg,0.09mmol) was added to 1, 4-dioxane (20ml), magnetically stirred, replaced with nitrogen, and heated to 90 ℃ under nitrogen protection for 3h.TLC showed complete reaction of the starting materials, and the reaction solution was ready for use. Compound 10-4(0.72g,2.72mmol), Pd (dppf) Cl was added2(65mg,0.09mmol), 0.5mL of water, and reacted at 100 ℃ for 4 hours under nitrogen substitution. The reaction solvent was distilled off, and the residue was subjected to column chromatography to obtain 0.55g of a product.
Synthesis of Compounds 10-6:
10-5(0.17g,0.46mmol) and 4-hydroxypiperidine (0.098g,0.85mmol) are dissolved in dichloroethane, NaBH (OAc) is added3(0.82g,3.87mmol), stirred overnight at room temperature, NaHCO was added3The solution was extracted twice with DCM, the aqueous phase was extracted twice with DCM, the organic phases were combined, the solvent was evaporated off, and the residue was purified by thin layer chromatography to give compound 10-6(45 mg).
Synthesis of compound 10:
dissolving compound 10-6(0.045g) in MeOH (5ml), adding NaOH (6ml,1.5N) dropwise, reacting at room temperature for 1h, TLC showing complete reaction of the raw materials, adjusting pH to be weakly basic, DCM extracting (40 ml. times.2), combining organic phases, drying over anhydrous sodium sulfateConcentrating, and purifying by thin layer chromatography to obtain 0.013g pure product.1HNMR(CD3OD,400MHz):8.26(s,2H),7.06(d,J＝8.0Hz,1H),6.63(dd,J＝2.4,8.0Hz,1H),6.16(d,J＝2.4Hz,1H),5.32(m,1H),3.30(m,2H),2.66(m,4H),2.43(m,2H),2.15(m,4H),1.58(m,4H),1.39(m,6H),1.17(m,3H)。ESI-MS m/z 424.2(M ++H)。
Example 11 preparation of compound (11):
synthesis of Compound 11-2:
compound 11-1(2.00g,8.84mmol) was dissolved in thionyl chloride (8ml) and heated under reflux for about 2 hours, concentrated under vacuum to remove excess thionyl chloride, the residue was taken up 2 times with dichloromethane to remove traces of thionyl chloride to give an oil, dissolved in dichloromethane (100ml), heated under reflux, aluminum trichloride (1.29g,9.72mmol) added in portions, refluxed overnight after the addition was complete, poured into 150ml of ice water, separated, the organic layer extracted with dichloromethane (40ml) and combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give the crude product. The crude product was subjected to column chromatography to give 2.10g, yield: 100 percent.
Synthesis of Compound 11-3:
phosphorus oxychloride (6.62g,0.043mol) and DMF (1ml) were added to a 25ml single neck flask, placed in an ice water bath to cool, and after stirring for 30min, Compound 11-2(2.20g,10.8mmol) was added. Stirring at room temperature for 30min, moving to a 90 ℃ oil bath pot, heating, after 2h, monitoring complete conversion of the raw materials by TLC, pouring the reaction liquid into ice water (50ml), adding EA (50ml), separating liquid, extracting an aqueous layer with EA (20ml), combining organic layers, washing once with saturated sodium bicarbonate (20ml), washing once with saturated sodium chloride (20ml), drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and carrying out column chromatography on the crude product to obtain 0.600g (PE: EA is 10:1to 5: 1).
Synthesis of Compounds 11-5:
compound 11-3(0.25g,1mmol),11-4(0.33g,1.1mmol), potassium carbonate (0.276g,2mmol), Pd (dppf) Cl2(0.073g,0.1mmol) was dissolved in 1, 4-dioxane (15 ml)/water (3ml), nitrogen was substituted 3 times, heated under reflux for 1.5h, and the residue was concentrated in vacuo and separated by column chromatography (PE: EA: 3:1) to give 0.178 g of an oil.
Synthesis of Compounds 11-6:
compound 11-5(0.175g, 0.44mmol), 4-methyl-4-hydroxypiperidine (0.089g, 0.88mmol), NaBH (OAc)3(1.866g, 8.8mmol), dissolved in 1, 2-dichloroethane (15ml), stirred at room temperature for 19 hours, added saturated sodium bicarbonate solution (100ml), separated, the aqueous layer extracted 2 times with dichloromethane (50ml), combined organic layers, dried over anhydrous sodium sulfate, spun dry, and the crude product purified by preparative plate to give 0.050g of compound 11-6.
Synthesis of compound 11:
compound 11-6(0.050g) was dissolved in methylene chloride (15ml), cooled to-10 ℃ and then boron tribromide (0.5ml) was slowly added to the solution to conduct a reaction at 0 ℃ for 10 min. Methanol (0.5ml) was added to quench the reaction, saturated sodium bicarbonate (30ml) was added, dichloromethane was extracted (20 ml. times.3), the organic layer was concentrated to give a crude product, and the crude product was isolated on a plate to give 0.015g of the desired product.1H NMR(400MHz,CD3OD):7.40(d,J＝8.0Hz,2H),7.20(d,J＝8.0Hz,2H),6.94(d,J＝11.6Hz,1H),6.32(d,J＝8.8Hz,1H),3.55(m,2H),3.35(m,2H),2.70(m,4H),2.56(m,2H),2.18(m,4H),1.63(m,4H),1.25(m,4H),1.18(m,6H)。 +ESI-MS m/z481.2(M+H)。
Example 12 preparation of compound (12):
synthesis of Compound 12-2:
compound 12-1(3.000g,0.0117mol) was dissolved in THF (40ml), purged with nitrogen, and LiAlH was added4(1.867g,0.0467mol), magnetic stirring reaction for 3h.TLC shows that the raw material is not reacted completely, heating up to 60 ℃ for reaction for 2h.TLC shows that the raw material is reacted completely, quenching, EA extraction (80ml multiplied by 3), organic phase combination, anhydrous sodium sulfate drying, concentration, column chromatography purification to obtain 2.264g, yield: 84%.
Synthesis of Compounds 12-3:
compound 12-2(2.264g,9.9mmol), pinacol diboron (3.012g,11.8mmol), KOAc (1.929g,19.8mmol) were added to 1, 4-dioxane (50ml), magnetically stirred, replaced with nitrogen, and Pd (dppf) Cl was added2(0.723g,1mmol), reacting for 2.5h under nitrogen protection and heating up to 83 ℃, and performing column chromatography purification to obtain 2.600g of product with yield of 95%.
Synthesis of Compounds 12-5:
to the reaction mixture of Compound 12-3, 12-4(0.250g,0.9mmol) and water (0.5ml) were added, the mixture was purged with nitrogen, and Pd (dppf) Cl was added2(0.069g,0.09mmol), reacting for 3h under the protection of nitrogen, heating up to 83 ℃, and performing TLC to show that the raw material 4 completely reacts, wherein the product is obtained by column chromatography separation in 0.220g, and the yield is 64%.
Synthesis of Compounds 12-6:
compound 12-5(0.220g,0.6mmol), 4-hydroxy-4-methylpiperidine (0.134g,1.2mmol) are dissolved in 1, 2-dichloroethane (12ml), the mixture is stirred for 30min under nitrogen substitution, and NaBH (OAc) is added3(1.232g,5.8mmol) and reacted at room temperature overnight TLC showed complete reaction of the starting material, saturated sodium bicarbonate solution and DCM (50ml/40ml) were added and the aqueous phase was separated, extracted with DCM (40 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and isolated by thin layer chromatography to give 0.040g pure product with 14% yield.
Synthesis of compound 12:
dissolving the compound 12-6(0.040g,0.08mmol) in MeOH (5ml), adding NaOH (3ml,2N) dropwise, reacting for 1h at room temperature, TLC shows that the raw materials are completely reacted, adjusting the pH to be alkalescent, performing DCM extraction (40ml × 2), combining organic phases, drying over anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.013g of pure product with the yield of 37%.1H NMR(400MHz,CD3OD):7.44(d,J＝7.6Hz,2H),7.07(m,3H),6.62(m,1H),6.23(d,J＝2.4Hz,1H),3.77(m,2H),3.59(s,2H),3.13(m,2H),2.92(m,2H),2.72(m,2H),2.19(m,4H),1.71(m,4H),1.31(s,6H),1.21(s,3H)。 +ESI-MS m/z436.2(M+H)。
Example 13 preparation of compound (13):
synthesis of Compound 13-2:
the compound 13-1(0.500g,2.4mmol), trifluoroethylamine (0.490g,4.8mmol), TBTU (1.192g,3.7mmol) and DIPEA (0.958g,7.4mmol) were dissolved in DCM (15ml), magnetically stirred under nitrogen, reacted at room temperature for 4h.TLC showed complete reaction of the starting material, purified by column chromatography to give 0.654g of product in 93% yield.
Synthesis of Compound 13-3:
dissolving the compound 13-2(0.654g and 2.3mmol) in DMF (14ml), replacing nitrogen for protection, adding NaH (0.111g and 4.6mmol), magnetically stirring for 0.5h, adding iodoethane (0.900g and 5.8mmol), heating to 80 ℃ for reaction for 3h, reacting by TLC to show that the raw material is completely reacted, quenching, adding EA and water (150ml/150ml), separating, extracting by EA (150ml multiplied by 2), combining organic phases, washing by saturated saline, drying by anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain 0.635g, wherein the yield is 89%.
Synthesis of Compound 13-4:
compound 13-3(0.630g,2.0mmol), pinacol diboron (0.617g,2.4mmol), KOAc (0.398g,4.1mmol) were added to 1, 4-dioxane (20ml), magnetically stirred, replaced with nitrogen, and Pd (dppf) Cl was added2(0.148g,0.24mmol), reacting for 3h at 83 ℃ under the protection of nitrogen, and directly using in the next step.
Synthesis of Compounds 13-6:
to the reaction mixture of Compound 13-4, 13-5(0.411g,1.6mmol) and water (1ml) were added, magnetic stirring was conducted, nitrogen gas was substituted, and Pd (dppf) Cl was added2(0.114g,0.2mmol), reacting for 3h under the protection of nitrogen and heating up to 83 ℃, and performing column chromatography separation to obtain 0.925g of a product.
Synthesis of Compounds 13-7:
dissolving compound 13-6(0.250g,0.5mmol), 4-hydroxypiperidine (0.125g,1.1mmol) in 1, 2-dichloroethane (12ml), stirring for 30min under nitrogen substitution, adding NaBH (OAc)3(1.151g,5.4mmol) and reacted at room temperature overnight TLC showed complete reaction of the starting material, saturated sodium bicarbonate solution and DCM (50ml/40ml) were added and the aqueous phase was separated, extracted with DCM (50 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and isolated by thin layer chromatography to give 0.090g pure product with yield: 32%.
Synthesis of compound 13:
dissolving the compound 13-7(0.090g,0.16mmol) in MeOH (5ml), adding NaOH (4ml,2N) dropwise, reacting at room temperature for 1h, TLC (thin layer chromatography) shows that the raw materials are completely reacted, adjusting the PH to be alkalescent, extracting with DCM (20ml × 3), combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.030g of pure product with the yield of 36%.1HNMR(400MHz,CD3OD):8.39(m,1H),7.72(m,2H),7.11(d,J＝7.2Hz,1H),6.65(m,1H),6.16(d,J＝1.2Hz,1H),4.64(m,1H),4.33(m,1H),3.63(m,2H),3.48(m,2H),2.90-2.73(m,6H),2.22(m,4H),1.67(m,4H),1.23(s,3H),1.19(s,3H)。 +ESI-MS m/z518.2(M+H)。
Example 14 preparation of compound (14):
synthesis of Compound 14-2
Compound 14-1(1.00g,4.69mmol), pinacol diboron (1.79g,7.04mmol), potassium acetate (966mg,9.85mmol) were dissolved in 20mL dioxane, N2Exchanging air for 3 times under protection, and adding Pd (dppf) Cl compound2(343mg,0.469mmol), gas replacement 3 times, heating and stirring at 90 ℃ for reaction for 3h, monitoring by TLC, after the reaction is finished, spin-drying the organic solvent, extracting with dichloromethane (15 mL. times.3), combining the organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating and evaporating to dryness, and separating by thin layer chromatography to obtain 1.5g of a product with the yield of 81.3%.
Synthesis of Compound 14-4:
compound 14-2(2.50g,9.6mmol), compound 14-3(1.70g,6.4mmol), potassium carbonate (2.65g,19.2mmol) were dissolved in dioxane (25mL) and water (5mL), N2Protecting the lower part and ventilating for 3 times, addingInto the compound Pd (dppf) Cl2(68mg,0.64mmol), gas replacement for 3 times, heating and stirring at 90 ℃ for reaction for 3 hours, monitoring by TLC, after the reaction is finished, spin-drying the organic solvent, extracting with dichloromethane (15mL multiplied by 3), combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating and evaporating to dryness, and separating by thin-layer chromatography to obtain 1.26g of a product.
Synthesis of Compounds 14-5:
dissolving 14-4(358mg,0.98mmol) and 4-hydroxy-4-methylpiperidine (227mg,1.98mmol) in 1, 2-dichloroethane (15mL), stirring for 30min, adding sodium borohydride acetate (2.09g,9.88mmol), stirring overnight at room temperature, TLC to monitor the reaction completion, adding saturated sodium bicarbonate solution (20mL), dichloromethane (15 mL. times.3) for extraction, combining organic phases, washing the organic phase with saturated sodium chloride solution (20mL), drying and concentrating with anhydrous sodium sulfate, separating with a preparative plate to obtain 120mg of the product.
Synthesis of Compounds 14-6:
dissolving 14-5(120mg,0.26mmol) of the compound in 5mL of methanol, adding 4mL of 10% sodium hydroxide solution, stirring at room temperature for reaction for 30min, monitoring the reaction of the raw materials by TLC, adjusting the pH to about 7 by using 1N hydrochloric acid, extracting by dichloromethane, washing an organic phase by using saturated sodium bicarbonate, combining the organic phases, drying by using anhydrous sodium sulfate, concentrating and evaporating to dryness, and performing thin-layer chromatography to obtain 84mg of a product.
Synthesis of compound 14:
dissolving (84mg,0.20mmol) compound 14-6 in 5mL anhydrous tetrahydrofuran, slowly adding 1.0mL (2.0M) tetrahydrofuran solution of ethyl magnesium bromide under nitrogen protection under ice bath condition, continuing to react for 1h after dropping, monitoring by TLC, pouring saturated ammonium chloride into the reaction solutionQuenching, extracting with ethyl acetate (15mL multiplied by 3), combining organic phases, drying with anhydrous sodium sulfate, concentrating, evaporating and separating by thin layer chromatography to obtain the product 40 mg.1H-NMR(CD3OD,400MHz):7.43(d,J＝8Hz,2H),7.10-7.07(m,3H),6.62(dd,J＝2.4Hz,J＝8Hz,1H),6.26(d,J＝2.4Hz,1H),3.69(m,2H),3.08-2.73(m,6H),2.20(m,4H),1.86-1.65(m,7H),1.20(s,4H),0.77(m,6H)。 +ESI-MS m/z 450.2(M+H)。
Example 15 preparation of compound (15):
synthesis of Compound 15-2:
compound 15-1(0.534g,2mmol), pinacol diboron (0.700g,2.8mmol), KOAc (0.624g,6mmol) were added to 15mL1, 4-dioxane, magnetically stirred, purged with nitrogen, and Pd (dppf) Cl was added2(0.166g,0.2mmol), reacting for 3h under nitrogen protection and heating to 90 ℃, wherein TLC shows that the reaction is complete and the reaction solution is ready for use.
Synthesis of Compounds 15-4:
to the reaction mixture of Compound 15-2 were added 15-3(0.472g,1.8mmol), potassium carbonate (0.824g,6mmol) and water (1ml), and the mixture was purged with nitrogen and added Pd (dppf) Cl2(0.170g,0.2mmol), reacting for 3h under the protection of nitrogen, heating to 90 ℃, and performing column chromatography to obtain 0.730g of product with the yield of 98 percent, wherein the reaction is complete as shown by TLC.
Synthesis of Compounds 15-5:
compound 15-4(0.145g,0.35mmol), 4-hydroxypiperidine (0.076g,0.75mmol) were dissolved in 1, 2-dichloroethane (10ml), purged with nitrogen, stirred for 30min, and NaBH (OAc) was added3(0.791g,3.7mmol), reaction overnight at room temperature saturated sodium bicarbonate solution and DCM (30ml/30ml) were added and the reaction solution was partitionedThe solution and the aqueous phase were extracted with DCM (30 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by thin layer chromatography to obtain 0.050g of pure product with a yield of 28%.
Synthesis of compound 15:
dissolving the compound 15-5(0.050g,0.1mmol) in MeOH (5ml), dropwise adding NaOH (1ml,1.0N), reacting at room temperature for 1h, TLC (thin layer chromatography) shows that the raw materials are completely reacted, adjusting the pH to be alkalescent, extracting DCM (30ml multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.030g of pure product with the yield of 66%.1H-NMR(CD3OD,400MHz):7.57(d,J＝8Hz,2H),7.17-7.08(m,3H),6.62(m,1H),6.21(d,J＝2.4Hz,1H),3.78-3.64(m,3H),3.12(m,2H),2.73(t,J＝6.4Hz,4H),2.21(m,4H),1.92(m,2H),1.71(m,2H),1.61(s,6H)。ESI-MS +m/z 460.2(M+H)。
Example 16 preparation of compound (16):
synthesis of Compound 16-2:
isoamyl alcohol (3.511g,0.018mol) is dissolved in DMF (40ml), NaH (0.817g,0.034mol) is added, nitrogen protection reaction is carried out for 2h, compound 16-1(2.000g,0.0227mol) is added, reaction is carried out at room temperature overnight, quenching is carried out, EA extraction (150ml multiplied by 2) is carried out, organic phases are combined, washing is carried out by using brine, drying is carried out by using anhydrous sodium sulfate, concentration is carried out, and column chromatography purification is carried out to obtain 1.100g of product, wherein the yield is 25%.
Synthesis of Compound 16-3:
compound 16-2(1.100g,4.5mmol), pinacol diboron (1.368g,5.3mmol), KOAc (0.881g,8.9mmol) were added to 50mL dioxane, replaced with nitrogen, and Pd (dppf) Cl was added2(0.328g,0.45mmol), nitrogen protection, reaction at 90 ℃ for 3h.TLC shows the originalThe reaction is completed and the reaction liquid is ready for use.
Synthesis of Compounds 16-5:
to the reaction mixture of Compound 16-3, 16-4(0.250g,0.9mmol) and water (1ml) were added, the mixture was purged with nitrogen, and Pd (dppf) Cl was added2(0.150g,0.2mmol), reacting for 3h at 90 ℃ under the protection of nitrogen. The product of 0.300g is obtained by column chromatography separation, and the yield is 81 percent.
Synthesis of Compounds 16-6:
compound 16-5(0.300g,0.76mmol), 4-hydroxypiperidine (0.175g,1.5mmol) were dissolved in 1, 2-dichloroethane (15ml), purged with nitrogen, stirred for 30min, and NaBH (OAc) was added3(1.612g,7.6mmol), reaction at room temperature overnight, adding saturated sodium bicarbonate solution and DCM (60ml/60ml), separating, extracting aqueous phase with DCM (50 ml. times.2), combining organic phases, drying over anhydrous sodium sulfate, concentrating, and separating by thin layer chromatography to obtain 0.055g pure product with yield: 15%.
Synthesis of compound 16:
dissolving a compound 16-6(0.055g,0.11mmol) in MeOH (5ml), dropwise adding NaOH (6ml,0.4N), reacting at room temperature for 1h, TLC (thin layer chromatography) shows that the raw materials are completely reacted, adjusting the pH to be alkalescent, performing DCM extraction (30ml multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.019g of a pure product with the yield of 38%.1H-NMR(CD3OD,400MHz):8.23(s,2H),7.05(d,J＝8.4Hz,1H),6.60(m,1H),6.13(d,J＝2.8Hz,1H),2.65(m,3H),2.45(m,2H),2.12(m,4H),1.73(m,4H),1.56(m,4H),1.25(s,4H),1.15(s,3H),0.94(t,J＝7.2Hz,6H)。ESI-MS +m/z 452.2(M+H)。
Example 17 preparation of compound (17):
synthesis of Compound 17-2
Compound 17-1 (1.50g,7.39mmol), trifluoroethylamine (1.46g,14.78mmol), TBTU (3.56g,11.09mmol), DIPEA (11.0mL) were dissolved in 15mL of dichloromethane, stirred at room temperature overnight for reaction, TLC monitored for completion of reaction, extracted with dichloromethane (15 mL. times.3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and isolated by column chromatography to give 2.4 g.
Synthesis of Compound 17-3:
dissolving a compound 17-2(500mg,1.76mmol) in 15mL of anhydrous DMF, adding sodium hydrogen (140mg,3.52mmol) in batches at room temperature, stirring for reaction for 30min, slowly dropwise adding iodoethane (0.35mL,4.4mmol), heating to 80 ℃ after dropwise adding to react for 3h, monitoring the reaction completion by TLC, pouring the reaction solution into 100mL of saturated ammonium chloride solution for quenching, extracting with ethyl acetate (15mL multiplied by 3), combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating and evaporating to dryness to obtain a product 600 mg.1H-NMR(CDCl3,400MHz):8.88(s,2H),4.24-4.17(m,2H),3.41(q,2H,J＝7.2Hz),1.15(t,3H,J＝7.2Hz)。
Synthesis of Compounds 17-6:
compound 17-3(550mg,1.76mmol), pinacol diboron (537mg,3.52mmol), potassium acetate (604mg,6.16mmol) were dissolved in 10mL dioxane, and Pd (dppf) Cl was added2(129mg,0.176mmol), displacing gas 3 times, heating and stirring at 90 ℃ for reaction for 3h, monitoring by TLC, adding compound 17-5(388mg,1.47mmol), Pd (dppf) Cl2(107mg,0.176mmol) and 2mL of water under protection of N2, continuing the reflux reaction for 2h, monitoring the completion of the reaction by TLC, and spin-drying the reaction solvent, siliconAnd (4) performing gel column chromatography on the PE, namely EA is 1: 1to obtain 409mg of a product.
Synthesis of Compounds 17-7:
dissolving the compound 17-6(278mg,0.60mmol) and 4-hydroxy-4-methylpiperidine (139mg,1.2mmol) in 1, 2-dichloroethane (10mL), stirring for reaction for 30min, adding sodium borohydride acetate (1.28g,6.0mmol), stirring at room temperature overnight, monitoring by TLC to complete the reaction, adding saturated sodium bicarbonate solution (20mL), extracting and separating by dichloromethane (15mL multiplied by 3), combining organic phases, washing the organic phases by saturated sodium chloride solution (20mL), drying and concentrating by anhydrous sodium sulfate, separating by preparative plates to obtain 80mg of a product with the yield of 24.5%.
Synthesis of compound 17:
dissolving the compound 17-7(80mg,0.15mmol) in 5mL of methanol, adding 4mL of 10% sodium hydroxide solution, stirring at room temperature for reaction for 30min, monitoring the reaction of the raw materials by TLC, adjusting the pH to about 7 by using 1N hydrochloric acid, extracting by dichloromethane, washing an organic phase by using saturated sodium bicarbonate, combining the organic phases, drying by using anhydrous sodium sulfate, concentrating and evaporating to dryness, and performing thin-layer chromatography to obtain a product 70 mg.1H-NMR(CD3OD,400MHz):8.65(s,2H),7.11(d,J＝8Hz,1H),6.66(m,1H),6.16(d,J＝2Hz,1H),4.49-4.32(m,2H),3.75-3.46(m,2H),3.35-3.23(m,2H),2.69(s,br,4H),1.56(s,4H),1.29(s,2H),1.17(s,4H)。ESI-MS +m/z 519.2(M+H)。
Example 18 preparation of compound (18):
synthesis of Compound 18-2:
compound 18-1(0.900g,3.5mmol), pinacol diboron (1.063g,4.2mmol), KOAc (0.685g,7mmol) were charged in 40mL dioxane, and placed under nitrogenAlternatively, Pd (dppf) Cl is added2(0.255g,0.35mmol), reacting for 3h under nitrogen protection and heating to 90 ℃, wherein TLC shows that the reaction is complete and the reaction solution is ready for use.
Synthesis of Compound 18-4:
to the reaction mixture of Compound 18-2, 18-3(0.400g,1.5mmol) and water (1ml) were added, the mixture was purged with nitrogen, and Pd (dppf) Cl was added2(0.110g,0.15mmol), reacting for 3h under nitrogen protection, heating to 90 ℃, and performing column chromatography to obtain 0.700g of crude product.
Synthesis of Compounds 18-5:
compound 18-4(0.300g,0.78mmol), 4-methyl-4-hydroxypiperidine (0.182g,1.6mmol) were dissolved in 1, 2-dichloroethane (15ml), purged with nitrogen, stirred for 30min, and NaBH (OAc) was added3(1.671g,16.5mmol) and reacted at room temperature overnight, saturated sodium bicarbonate solution and DCM (60ml/60ml) were added, the layers were separated, the aqueous phase was extracted with DCM (50 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by thin layer chromatography to give 0.077g pure product, yield: 19 percent.
Synthesis of compound 18:
dissolving the compound 18-5(0.077g,0.15mmol) in MeOH (5ml), dropwise adding NaOH (5ml,1.5N), reacting at room temperature for 1h, TLC shows that the raw materials are completely reacted, adjusting the pH to be alkalescent, DCM extracting (40ml multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.034g pure product with the yield of 49%.1H-NMR(CD3OD,400MHz):8.64(s,2H),7.12(d,J＝8.4Hz,1H),6.67(m,1H),6.17(d,J＝2.4Hz,1H),3.61(m,2H),2.72-2.50(m,7H),2.21(m,5H),1.59(s,4H),1.21(s,6H),1.19(s,3H)。 +ESI-MS m/z 465.2(M+H)。
Preparation of compound (19) of example 19:
synthesis of Compound 19-2:
compound 19-1(1.00g,4.97mmol), trifluoroethylamine (0.986g,9.95mmol), TBTU (2.40g,7.46mmol), DIPEA (2.47mL) were dissolved in 15mL dichloromethane, stirred overnight at room temperature, TLC monitored for reaction completion, extracted with dichloromethane (15mL × 3), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and chromatographed on silica gel to give 1.5 g.
Synthesis of Compound 19-3:
dissolving a compound 19-2(871mg,3.09mmol) in 15mL of anhydrous THF, adding sodium hydrogen (250mg,6.18mmol) in batches at room temperature, stirring for reaction for 30min, slowly dropwise adding iodoethane (0.3mL,3.71mmol), heating and refluxing for 3h after dropwise addition, monitoring the reaction completion by TLC, pouring the reaction liquid into 100mL of saturated ammonium chloride solution for quenching, extracting the combined organic phase by using ethyl acetate (15mL multiplied by 3), washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating and evaporating to dryness to obtain 1.48g of a product.
Synthesis of Compound 19-4:
compound 19-3(1.48g,4.75mmol), pinacol diboron (1.81g,7.14mmol), potassium acetate (980mg,0.01mol) were dissolved in 20ml dioxane, N2Exchanging air for 3 times under protection, and adding Pd (dppf) Cl2(350mg,0.476mmol), gas is replaced for 3 times, the mixture is heated and stirred at 90 ℃ for reaction for 3 hours, TLC monitoring is carried out, after the reaction is finished, the organic solvent is dried in a spinning mode, dichloromethane (15mL multiplied by 3) is used for extraction, the organic phases are combined, saturated saline solution is used for washing, anhydrous sodium sulfate is dried, concentration and evaporation are carried out, thin layer chromatography separation is carried out, 1.5g of the product is obtained, and the yield is 88.8%.
Synthesis of Compounds 19-6:
dissolve compound 19-4(328mg,0.92mmol), compound 19-5(200mg,0.76mmol), potassium carbonate (367mg,2.66mmol) in dioxane (8mL) and water (2mL), N2Exchanging air for 3 times under protection, and adding Pd (dppf) Cl2(56mg,0.076mmol), replacing nitrogen for 3 times, heating and stirring at 90 ℃ for reaction for 3 hours, monitoring by TLC, after the reaction is finished, spin-drying the organic solvent, extracting with dichloromethane (15mL multiplied by 3), combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating and evaporating to dryness, and separating by column chromatography to obtain 400mg of a product with the yield of 100%.
Synthesis of Compounds 19-7:
dissolving the compound 19-6(300mg,0.69mmol) and 4-hydroxy-4-methylpiperidine (160mg,1.38mmol) in 1, 2-dichloroethane (10mL) and stirring for reaction for 30min, adding sodium borohydride acetate (1.47g,6.9mmol), stirring at room temperature overnight for reaction, monitoring the reaction by TLC, adding saturated sodium bicarbonate solution (20mL), extracting and separating by dichloromethane (15mL multiplied by 3), combining organic phases, washing the organic phase by saturated sodium chloride solution (20mL), drying and concentrating by anhydrous sodium sulfate, separating by a preparative plate to obtain 114mg of a product with the yield of 29.6%.
Synthesis of compound 19:
dissolving a compound 19-7(114mg,0.21mmol) in 10mL of dichloromethane, slowly dropwise adding 0.5mL of boron tribromide solution under the protection of nitrogen under the condition of ice bath, continuing to react for 30min after dropwise addition, monitoring by TLC that the reaction of raw materials is finished, adding 2mL of methanol to quench the reaction, extracting and separating dichloromethane (15mL multiplied by 3), combining organic phases, washing the organic phase with a saturated sodium bicarbonate solution (20mL), drying and concentrating, separating a preparation plate, and obtaining a productProduct 40 mg.1H-NMR(CD3OD,400MHz):7.47(d,J＝7.6Hz,2H),7.28(d,J＝8Hz,2H),7.01(d,J＝8.4Hz,1H),6.64(m,1H),6.24(d,J＝2.8Hz,1H),4.35-4.29(m,2H),3.67-3.51(m,4H),3.10-3.05(m,1H),2.84-2.72(m,4H),2.7-2.2(m,4H),1.76-1.67(m,3H),1.22(s,3H),1.17-1.14(m,3H)。 +ESI-MS m/z 517.2(M+H)。
Example 20 preparation of compound (20):
synthesis of Compound 20-2:
compound 20-1(0.900g,3.5mmol), pinacol diboron (1.063g,4.2mmol), KOAc (0.685g,7mmol) were added to 1, 4-dioxane, magnetically stirred, purged with nitrogen, and Pd (dppf) Cl was added2(0.255g,0.35mmol), reacting for 3h under the protection of nitrogen, raising the temperature to 90 ℃, and indicating that the raw materials are completely reacted by TLC, wherein the reaction liquid is reserved.
Synthesis of Compounds 20-4:
to the reaction mixture of Compound 20-2, 20-3(0.400g,1.5mmol) and water (1ml) were added, the mixture was purged with nitrogen, and Pd (dppf) Cl was added2(0.110g,0.15mmol), reacting for 3h under the protection of nitrogen and heating to 90 ℃, and performing column chromatography separation to obtain 0.700g of crude product.
Synthesis of Compounds 20-5:
compound 20-4(0.250g,0.66mmol), 4-hydroxypiperidine (0.133g,1.3mmol) were dissolved in 1, 2-dichloroethane (15ml), purged with nitrogen, stirred for 30min, and NaBH (OAc) was added3(1.393g,6.6mmol), reacting at room temperature overnight, adding saturated sodium bicarbonate solution and DCM (60ml/60ml), separating, extracting the aqueous phase with DCM (50ml × 2), combining the organic phases, drying over anhydrous sodium sulfate, concentrating, separating by thin layer chromatography to obtain 0.120g pure product, and collectingRate: 37 percent.
Synthesis of compound 20:
dissolving the compound 20-5(0.120g,0.24mmol) in MeOH (5ml), dropwise adding NaOH (6ml,1.5N), reacting at room temperature for 1h, TLC (thin layer chromatography) shows that the raw materials are completely reacted, adjusting the pH to be alkalescent, DCM (40ml × 2) extracting, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.034g of a pure product with the yield of 31%.1H-NMR(CD3OD,400MHz):8.63(s,2H),7.11(d,J＝8.4Hz,1H),6.65(m,1H),6.18(d,J＝2.4Hz,1H),3.63(m,3H),2.73-2.52(m,7H),2.23(m,5H),1.61(m,4H),1.22(m,6H)。 +ESI-MSm/z451.2(M+H)。
Example 21 preparation of compound (21):
synthesis of Compound 21-2:
compound 21-1(1.00g,4.69mmol), pinacol diboron (1.79g,7.04mmol), potassium acetate (966mg,9.85mmol) were dissolved in 20mL dioxane, N2The gas was replaced 3 times, and Pd (dppf) Cl was added2(343mg,0.469mmol), gas displacement 3 times, heating at 90 ℃ and stirring for reaction for 3h, monitoring by TLC, after the reaction is completed, the organic solvent is dried by spinning, extraction is carried out with dichloromethane (15 mL. times.3), the organic phases are combined, washed with saturated brine, dried, concentrated and separated by column chromatography to obtain 1.5g of the product with the yield of 81.3%.
Synthesis of Compounds 21-4:
dissolving compound 21-2(824mg,3.17mmol), compound 21-3(500mg,2.11mmol), potassium carbonate (1.021g,7.40mmol) in dioxane (15mL) and water (3mL), N2Exchanging air for 3 times under protection, and adding Pd (dppf) Cl2(154mg,0.211mmol), displacing gas 3 times, heating at 90 deg.CStirring for reaction for 3h, monitoring by TLC, after the reaction is finished, spin-drying the organic solvent, extracting with dichloromethane (15 mL. times.3), combining the organic phases, washing with saturated saline, drying, concentrating, and separating by column chromatography to obtain 453mg of product with 42% yield.
Synthesis of Compounds 21-5:
dissolving the compounds 21-4(453mg,1.36mmol) and 4-hydroxypiperidine (274mg,2.72mmol) in 1, 2-dichloroethane (15mL), stirring for reaction for 30min, adding sodium borohydride acetate (2.87g,13.6mmol), stirring at room temperature overnight for reaction, monitoring the reaction by TLC, adding saturated sodium bicarbonate solution (20mL), extracting and separating by dichloromethane (15mL multiplied by 3), combining organic phases, washing the organic phase by saturated sodium chloride solution (20mL), drying and concentrating by anhydrous sodium sulfate, separating by a preparative plate to obtain 303mg of the product with the yield of 53%.
Synthesis of Compounds 21-6:
dissolving a compound 21-5(303mg,0.75mmol) in 15mL of dichloromethane, slowly dropwise adding 1.0mL of boron tribromide solution under the protection of nitrogen under the condition of ice bath, continuing to react for 30min after dropwise addition, monitoring the reaction completion of raw materials by TLC, adding 2mL of methanol to quench the reaction, extracting and separating dichloromethane (15mL multiplied by 3), combining organic phases, washing the organic phase with saturated sodium bicarbonate solution (20mL), drying and concentrating with anhydrous sodium sulfate, separating a preparation plate, and obtaining 100mg of a product.
Synthesis of compound 21:
dissolving compound 21-6(100mg,0.25mmol) in 10mL anhydrous tetrahydrofuran, slowly dropwise adding 2.0M tetrahydrofuran solution of ethyl magnesium bromide (2.5mL,5mmol) under ice bath condition under nitrogen protection, continuing to react for 1h after dropwise adding, monitoring by TLC, pouring the reaction solution into saturated ammonium chlorideQuenching, extracting with ethyl acetate (15 mL. times.3), combining organic phases, drying with anhydrous sodium sulfate, concentrating, evaporating to dryness, and separating by thin layer chromatography to obtain 34mg of product.1H-NMR(CD3OD,400MHz):7.43(d,J＝8.4Hz,2H),7.10-7.07(m,3H),6.62(m,1H),6.25(d,J＝2.4Hz,1H),3.77(s,1H),3.65(s,2H),3.09(s,2H),2.72(m,4H),2.23-2.19(m,4H),1.86-1.82(m,6H),1.70(m,2H),0.78(t,J＝7.2Hz,6H)。 +ESI-MSm/z436.2(M+H)。
Example 22 preparation of compound (22):
synthesis of Compound 22-3:
compound 22-1(0.512g,1.7mmol),22-2(0.400g,1.7mmol), K2CO3(0.698g,5.1mmol) was added to 1, 4-dioxane/water (15ml/1ml), magnetically stirred, replaced with nitrogen, and Pd (dppf) Cl was added2(0.136g,0.2mmol), reacting for 3h under the protection of nitrogen, heating to 90 ℃, and performing column chromatography to obtain 0.621g of product with the yield of 97 percent, wherein the TLC shows that the raw material 2 completely reacts.
Synthesis of Compound 22-4:
compound 22-3(0.621g,1.6mmol), 4-methyl-4-hydroxypiperidine (0.378g,3.3mmol) were dissolved in 1, 2-dichloroethane (10ml), purged with nitrogen, stirred for 30min, and NaBH (OAc) was added3(3.487g,16.5mmol) and reacted at room temperature overnight, saturated sodium bicarbonate solution and DCM (60ml/60ml) were added, the layers were separated, the aqueous layer was extracted with DCM (50 ml. times.2), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and isolated by thin layer chromatography to give 0.260g pure product, yield: 34 percent.
Synthesis of compound 22:
compound 22-4(0.260g,0.55mmol) was dissolved in DCM (10ml) and purifiedThe temperature is raised to 0 ℃, BBr is dripped3(0.6ml), reacting at low temperature for 30min, TLC shows that the raw materials react completely, quenching, adding saturated sodium bicarbonate solution and DCM (40ml/40ml), separating, extracting the aqueous phase with DCM (40ml × 2), combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and purifying by thin layer chromatography to obtain 0.080g pure product with yield of 32%.1H-NMR(CD3OD,400MHz):7.45(d,J＝8.4Hz,2H),7.27(d,J＝8.0Hz,2H),7.11(d,J＝8.4Hz,1H),6.65(m,1H),6.25(d,J＝2.4Hz,1H),3.88(m,2H),3.57(m,2H),3.35(m,3H),2.97(m,2H),2.74(m,2H),2.25(m,4H),1.87-1.75(m,4H),1.28-1.15(m,10H)。 +ESI-MS m/z463.2(M+H)。
Example 23 preparation of compound (23):
synthesis of Compound 23-3:
compounds 23-1(0.27g,1.03mmol), 23-2(0.225g,0.68mmol), potassium carbonate (0.335g,2.43mmol), Pd (dppf) Cl2(0.059g,0.08mmol) is placed in a bottle, 25mL of dioxane and 1mL of water are added, nitrogen is replaced for protection, the temperature is heated to 90 ℃ for reaction for 2 hours, the temperature is reduced to room temperature, the reaction solvent is evaporated, and the residue is separated and purified by column chromatography to obtain about 200mg of product.
Synthesis of Compound 23-4:
compound 23-3(0.20g,0.49mmol) and 4-hydroxypiperidine (0.10g,0.98mmol) are dissolved in 1, 2-dichloroethane, and NaBH (OAc) is added3(0.623g,2.94mmol), stirred overnight at room temperature, NaHCO was added3The solution was extracted twice with DCM, the aqueous phase was extracted twice with DCM, the organic phases were combined and the solvent was evaporated off to give 250mg of crude product.
Synthesis of compound 23:
dissolving compound 23-4(0.25g,0.49mmol) in methanol (10mL), adding NaOH solution (2mL,1N), stirring at room temperature, detecting by TLC after half an hour, adding hydrochloric acid for acidification, and adding NaHCO3The mixture was extracted twice with DCM, the aqueous phase was extracted twice with DCM, the organic phases were combined, the solvent was evaporated off, and the residue was purified by thin layer chromatography to give 65mg of Compound 23. The yield thereof was found to be 26%.1HNMR(CD3OD,400MHz):7.16(d,J＝7.6,1H),7.01(m,3H),6.57(m,1H),6.28(d,J＝3.6,1H),4.58(s,1H),3.70(s,3H),3.37(m,2H),3.31(m,2H),3.22(m,2H),3.01(m,4H),2.65(m,1H),2.19(m,5H),1.84(m,2H),1.62(m,2H),1.29(m,6H)。 +ESI-MSm/z479.2(M+H)。
Comparative example 1
Example 24: compound DOR receptor activity and half-life assays
The following tests were carried out for compounds 1to 23 prepared in examples 1to 23 and compound 24 of comparative example 1:
DOR receptor activity assay: after the test compound is incubated with the DOR receptor, the receptor activity of the compound is detected by a calcium flux functional assay.
2. Half life of drug (HLM T)1/2) And (3) testing: in a 96-well plate, 10uL of the test compound was added, and then each of the human liver microsome solutions was added, followed by incubation at 37 ℃ for 10 minutes. Then adding NADPH (reduced nicotinamide adenine dinucleotide phosphate), culturing for a certain time, and adding a stop solution to terminate the reaction. The samples were centrifuged at 4000rpm for 20min, the supernatant sampled for LC/MS/MS determination and T calculated1/2。
3. The test results are shown in table one.
Watch 1
As can be seen from the table, compounds 1to 23 according to the invention have a significantly more ideal half-life than comparative compound 24. And the activity of these compounds was either comparable to or significantly improved over that of comparative compound 24. Overall, it is expected that the compounds according to the present invention are more ideal therapeutic agents for alzheimer-related diseases.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (3)
1. An opioid receptor antagonist, which is one selected from the group consisting of compounds represented by the following structures and pharmaceutically acceptable salts thereof,
2. use of an opioid receptor antagonist according to claim 1 in the manufacture of a medicament for the prevention and/or treatment of diseases and conditions associated with alzheimer's disease.
3. A pharmaceutical composition for the prevention and/or treatment of alzheimer's related diseases and conditions, comprising an opioid receptor antagonist of claim 1.
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| EP4228758B1 (en) * | 2020-10-19 | 2024-07-24 | Sanofi | Substituted 6,7-dihydro-5h-benzo[7]annulene compounds and their derivatives, processes for their preparation and therapeutic uses thereof |
| CA3196092A1 (en) * | 2020-10-19 | 2022-04-28 | Patrick Bernardelli | Substituted 6,7-dihydro-5h-benzo[7]annulene compounds and their derivatives, processes for their preparation and therapeutic uses thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61130286A (en) * | 1984-11-28 | 1986-06-18 | Suntory Ltd | 2,3-dihydro-1-benzoxepine derivative |
| CN1221743A (en) * | 1997-12-13 | 1999-07-07 | 格吕伦塔尔有限公司 | Substituted heterocyclic benzoeycloalkenes and the use thereof as substances having analgesic effect |
| US6022895A (en) * | 1997-03-14 | 2000-02-08 | Gruenenthal Gmbh | Substituted amino compounds and their use as substances having an analgesic effect |
| CN104844471A (en) * | 2015-04-21 | 2015-08-19 | 银杏树药业(苏州)有限公司 | Compound used as DOR receptor antagonist |
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| DE102004030099A1 (en) * | 2004-06-22 | 2006-01-12 | Grünenthal GmbH | Saturated and unsaturated 3-pyridylbenzocycloalkylmethylamines as serotonin and / or norepinephrine reuptake inhibitors and / or μ-opioid receptor modulators |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61130286A (en) * | 1984-11-28 | 1986-06-18 | Suntory Ltd | 2,3-dihydro-1-benzoxepine derivative |
| US6022895A (en) * | 1997-03-14 | 2000-02-08 | Gruenenthal Gmbh | Substituted amino compounds and their use as substances having an analgesic effect |
| CN1221743A (en) * | 1997-12-13 | 1999-07-07 | 格吕伦塔尔有限公司 | Substituted heterocyclic benzoeycloalkenes and the use thereof as substances having analgesic effect |
| CN104844471A (en) * | 2015-04-21 | 2015-08-19 | 银杏树药业(苏州)有限公司 | Compound used as DOR receptor antagonist |
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